ABSTRACT Immaturity of the immune system in neonates and infants represents an underlying factor for increased susceptibility to infection that threaten childhood. However, the exact mechanisms responsible for immaturity of the immune system remain to date uncharacterized. Work from my laboratory provided evidence that immaturity of Natural Killer (NK) cells is orchestrated by TGF?. We demonstrated that NK cells are able to complete maturation early in life if TGF?R signaling is blocked. A point of crucial consequence of this advantage is efficient control of cytomegalovirus infection in infant mice with NK cells lacking TGF?R signaling. The overall goal of this proposal is to elucidate the cellular and molecular mechanisms by which TGF? imposes constraints on NK cell immune maturation during infancy and to identify the factors upstream and downstream of TGF?R signaling that dictate the fate of infant NK cell immaturity. Three specific aims will be addressed in this proposal: (1) define the make-up of TGF? signaling pathway in infant NK cells, (2) determine whether hematopoiesis in early life is conducive to higher availability/activity of TGF?, and (3) establish the relationship between the prevalence of neonatal suppressor cells and immaturity of NK cells during infancy. The continuing high global burden of infections in children elucidates the need for on-going basic and translational studies in the area of neonatal and infant immune ontogeny. Distinct early life immune ontogeny will certainly have direct implications for current and future pediatric therapies. In that regard, this project holds substantial promise in unraveling new strategies that can be applied to unlock the NK cell deficit in early life, a deficit that was originally thought intangible.